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Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.

ABSTRACT: The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)-kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)-targeted therapy.In the Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). Perifosine 231 enrolled 2 groups that received daily oral perifosine (100 mg daily): Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor.In the Perifosine 228 trial, 1 patient achieved a partial response (objective response rate, 4%; 95% confidence interval, 0.7%-20%), and 11 patients (46%) had stable disease as their best response. The median progression-free survival was 14.2 weeks (95% confidence interval, 7.7-21.6 weeks). In the Perifosine 231 trial, 5 patients achieved a partial response (objective response rate, 10%; 95% confidence interval, 4.5%-22.2%) and 16 patients (32%) had stable disease as their best response. The median progression-free survival was 14 weeks (95% confidence interval, 12.9, 20.7 weeks). Overall, perifosine was well tolerated, and there were very few grade 3 and 4 events. The most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue.Although perifosine demonstrated activity in patients with advanced RCC after failure on VEGF-targeted therapy, its activity was not superior to currently available second-line agents. Nonetheless, perifosine may be worthy of further study in RCC in combination with other currently available therapies.

SUBMITTER: Cho DC

PROVIDER: S-EPMC3934426 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.

Cho Daniel C DC Hutson Thomas E TE Samlowski Wolfram W Sportelli Peter P Somer Brad B Richards Paul P Sosman Jeffrey A JA Puzanov Igor I Michaelson M Dror MD Flaherty Keith T KT Figlin Robert A RA Vogelzang Nicholas J NJ

Cancer 20120606 24

<h4>Background</h4>The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)-kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular ...[more]

PMID: 22674198

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Project description:Activation of the PI3K/Akt pathway is associated with the development of numerous human cancers. As a result, many emerging therapies target this pathway. Previous studies have shown that targeting the PI3K/Akt pathway at the level of PI3K is associated with a drop in phosphocholine (PCho) and a reduction in hyperpolarized lactate production. However, the consequences of targeting downstream of PI3K at the level of Akt have not been investigated. Perifosine is an anticancer alkylphospholipid used in clinical trials. It acts by inhibiting phosphorylation of Akt and has been shown to inhibit CTP-phosphocholine cytidyltransferase (CT). The goal of this study was to identify the MRS-detectable metabolic consequences of treatment with perifosine in MCF-7 breast cancer cells. We found that perifosine treatment led to a 51 ± 5% drop in PCho from 30 ± 5 to 15 ± 1 fmol/cell and a comparable drop in de novo synthesized PCho. This was associated with a drop in choline kinase (ChoK) activity and ChoKα expression. CT inhibition could not be ruled out but likely did not contribute to the change in PCho. We also found that intracellular lactate levels decreased from 2.7 ± 0.5 to 1.5 ± 0.3 fmol/cell and extracellular lactate levels dropped by a similar extent. These findings were consistent with a drop in lactate dehydrogenase expression and associated with a drop in activity of the hypoxia inducible factor (HIF)-1α. The drops in PCho and lactate production following perifosine treatment are therefore mediated downstream of Akt by the drop in HIF-1α, which serves as the transcription factor for both ChoK and lactate dehydrogenase. The metabolic changes were confirmed in a second breast cancer cell line, MDA-MB-231. Taken together, these findings indicate that PCho and lactate can serve as noninvasive metabolic biomarkers for monitoring the effects of inhibitors that target the PI3K/Akt pathway, independent of the step that leads to inhibition of HIF-1α.

Project description:Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits MET and AXL, both associated with poor prognosis in renal cell carcinoma (RCC), next to vascular endothelial growth factor receptor 2, KIT, FLT3 and RET. Chronic treatment with vascular endothelial growth factor receptor (VEGFR)-targeting sunitinib upregulates MET and AXL in RCC, indicating that cabozantinib may be particularly effective in patients with advanced RCC whose disease progressed on prior VEGFR-targeted treatment. Cabozantinib (60 mg once daily) has been investigated in comparison to everolimus (10 mg once daily) in a phase III randomized controlled trial (RCT) in 658 patients with advanced RCC of whom 71% had received one prior and 29% had received at least two prior lines of VEGR-targeted therapy. This study demonstrated highly significant improved progression-free survival of 7.4 months versus 3.9 months with a hazard ratio (HR) of 0.51 [95% confidence interval (CI) 0.41-0.62] in favour of cabozantinib. Cabozantinib also showed a superior overall survival of 21.4 months versus 16.5 months (HR 0.66; 95% CI 0.53-0.83). Objective response rate was higher in cabozantinib-treated patients, 17% versus 3%. Clinical benefit was shown in all subgroups of patients, including in patients with bone or visceral metastases. The safety profile was acceptable with manageable side effects. Based on this study, cabozantinib is a highly effective approved second-line treatment option for patients with advanced RCC with a manageable toxicity profile. Other recently approved second-line agents include checkpoint inhibitor nivolumab and VEGF-targeting agent lenvatinib combined with everolimus. In the absence of predictive markers as well as head-to-head comparisons of these three recently approved treatments, the choice between these drugs in second-line treatment will probably be made based on comorbidities, tolerability of previous treatment and presence of high tumour burden with rapidly progressive disease. Future pretreatment assessment of MET and AXL tumour aberration may aid clinicians to make a rational choice between currently approved second-line treatment options.

Dataset Information

Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.

Publications

Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy.

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